Neurologic outcomes after coronary artery bypass grafting with and without cardiopulmonary bypass

Neurologic Outcomes After Coronary Artery Bypass Grafting With and Without Cardiopulmonary Bypass John E. Scarborough, William White, Frantz E. Derilus, Joseph P. Mathew, Mark F. Newman, and Kevin P. Landolfo Neurologic injury, in the form of either stroke or more subtle neurocognitive impairment, is a frequent and potentially devastating complication of coronary artery bypass grafting (CABG). The etiology of CABGassociated neurologic injury is likely multifactorial, with the phenomena of cerebral hypoperfusion and embolism being the major contributors. Several perioperative strategies have been developed in an effort to reduce the incidence of CABG-associated neurologic complications. Hypothermic cerebral perfusion, alpha stat acid-base management, and slow patient rewarming have been shown by several investigators to minimize adverse neurologic sequelae associated with the use of cardiopulmonary bypass. Performing CABG without cardiopulmonary bypass (off-pump CABG), meanwhile, has been shown to reduce the risk of perioperative stroke, especially in high-risk patients such as the elderly. Whether off-pump CABG reduces the incidence of less severe neurocognitive impairment has not yet been clearly established and merits further investigation in the form of large, multicenter, randomized trials. Other technical innovations, such as the use of sutureless and clampless aortic anastomotic devices, also may be able to further minimize the neurologic complications associated with CABG. © 2003 Elsevier Inc. All rights reserved. Key Words: Coronary artery bypass grafting, cardiopulmonary bypass, stroke, neurocognitive dysfunction, cerebral embolism.

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ince its inception, coronary artery bypass grafting (CABG) has become the clinical standard for the treatment of multivessel coronary artery disease. As techniques in myocardial preservation and anesthetic management have improved, this procedure has become increasingly safe, with mortality rates declining to as low as 1-3% in recent reports.1 As a result, older patients and those with more severe cardiac compromise are now eligible for surgical coronary revascularization. Despite these improvements in surgical mortality, however, the risk of neurologic injury increases with advancing age, as shown in Fig 1.2 Therefore, the impact of postoperative neurologic dysfunction is unlikely to diminish in the future unless cardiac surgeons and anesthesiologists become more adept at preventing such complications. Neurologic complications after CABG can be classified into two groups. Type I injuries include From the Departments of Surgery and Anesthesiology, Duke University Medical Center, Durham, NC. Address reprint requests to Kevin P. Landolfo, MD, Duke University Medical Center Box 3675 Durham, NC 27710. © 2003 Elsevier Inc. All rights reserved. 1043-0679/03/1501-00007-8$30.00/0 doi:10.1016/S1043-0679(03)00007-8

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stroke, transient ischemic attack, coma, and stupor. These injuries are caused by specific and identifiable focal insults to the cerebral parenchyma. As a result, the diagnosis of type I injuries are achieved through standard clinical and radiographic assessment. The incidence of stroke after CABG procedures has been reported from 1-5%; however, in patients older than 80 years of age, the incidence may be as high as 10%.2,3 Type II neurologic injuries refer to new deterioration in intellectual function, including confusion, agitation, disorientation, memory deficit, or seizures and neurocognitive dysfunction. These types of injuries are much more prevalent than type I injuries and appear to manifest most strikingly in the immediate postoperative period. The incidence of neurocognitive impairment after CABG is highest at discharge (approximately 50-80%), declining to 20-40% at 6 weeks, and 10-30% at 6 months.4,5 Furthermore, a recent follow-up study of 261 CABG patients from the authors’ institution found that the incidence of cognitive dysfunction was as high as 42% 5 years after operation, indicating that this type of injury may persist or even worsen over long periods of time.6 Because of their subtle nature, these def-

Seminars in Thoracic and Cardiovascular Surgery, Vol 15, No 1 ( January), 2003: pp 52-62

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icant because patients who develop CABG-associated neurologic injury require significantly longer postoperative hospital stays and more extensive rehabilitation in intermediate and longterm facilities.9

Etiology of CABG-Associated Neurologic Injury

Figure 1. Age-related incidence of complications associated with coronary artery bypass grafting.

icits are not easily diagnosed based on standard clinical or radiographic criteria. Instead, the identification of neurocognitive deterioration requires that a complex battery of neuropsychological tests be performed both before and at some point after CABG. These tests assess a number of different cognitive domains, including memory, mood, attention, and constructive ability. There are a number of different possible methods for determining whether neurocognitive deterioration has occurred based on the results of these tests. A consensus committee organized to address the subject, defines a cognitive deficit as a 20% decrease in postoperative performance (relative to preoperative performance) in at least 20% of the tests administered.7 Regardless of how neurocognitive dysfunction is defined, however, this type of neurologic injury is common and its prevention has become the focus of intense clinical research. The negative impact of neurologic injury after CABG on patient outcome cannot be understated. In-hospital mortality rates for patients with either type I or type II neurologic injuries are significantly higher than in patients who suffer no adverse postoperative neurologic complications. Moreover, patients who develop postoperative stroke have significantly lower survival at 5 years than patients who do not suffer postoperative cerebrovascular ischemic events (44% and 81%, respectively).8 Neurocognitive dysfunction after CABG also significantly affects patient quality of life, leading to lower general health and a less productive working status for as long as 5 years after the procedure. Finally, the societal costs of this type of complication are also signif-

Determining the precise etiology of CABGassociated neurologic injury is difficult because multiple perioperative factors are likely to be significant. Furthermore, the mechanisms responsible for type I and type II neurologic injuries may be somewhat different. However, there are also likely to be similarities in the causes of these two types of postoperative neurologic compromise. For instance, patient age has been consistently identified as the single most important risk factor for both stroke and neurocognitive dysfunction.10 Other demographic characteristics also contribute to the risk of developing postoperative stroke. The Multicenter Study of Perioperative Ischemia Research Group has identified several patient-related characteristics, including age, history of diabetes, history of vascular or pulmonary disease, and presence of unstable angina, which they have used to develop a validated preoperative stroke risk index. This index allows the risk of stroke to be determined for each patient preoperatively within 95% confidence levels.11 Similarly, genetic factors may also increase the risk of developing postoperative neurocognitive dysfunction, such as the presence of mutations in the apolipoprotein E␧-4 gene. Preliminary evidence indicates that mutations in this gene are associated with a significantly increased risk of manifesting neurocognitive dysfunction after CABG.12 Although preoperative variables, such as age and genetic predisposition, cannot be altered, there are several perioperative risk factors for neurologic injury which, if identified and managed appropriately, may reduce the incidence of postoperative neurologic dysfunction.

Cerebral Embolism Cerebral embolism has been identified as a primary mechanism for the development of both stroke and neurocognitive dysfunction after CABG. In general, cerebral emboli can be classified based on size; macroemboli are those mea-

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suring 200 ␮m or greater in diameter, whereas microemboli are smaller and thus able to occlude smaller-caliber cerebral arterioles and capillaries. The major source of macroemboli is ascending aortic atherosclerotic disease. Debris from atherosclerotic plaques located in the ascending aorta become dislodged during manipulation of the aorta and progress downstream to eventually occlude large-caliber vessels within the cerebral vasculature, thereby causing focal cerebral ischemia. Evidence for aortic atherosclerosis as a risk factor for the development of postoperative stroke is overwhelming. In two large prospective studies of patients undergoing CABG at multiple institutions, atherosclerosis of the ascending aorta was the strongest independent risk factor for stroke.13,14 Other investigators have found that the degree of intimal thickening at the aortic arch and the size and mobility of overlying atherosclerotic plaques are directly related to the incidence of postoperative neurologic injury. Identification of macroemboli as the cause of postoperative stroke was provided by Mizuno and colleagues, who obtained computed tomography scans in a series of 79 patients who developed stroke after CABG at their institution. The majority of these scans identified new ischemic lesions within the distribution of large-caliber cerebral arteries, presumable caused by macroemboli from atherosclerotic lesions within the ascending aorta.15 Cerebral microembolism during CABG has been shown to be associated with the development of postoperative neurocognitive dysfunction. Pugsley16 described the direct relationship between the number of cerebral microemboli and the incidence of postoperative neurocognitive dysfunction. Transcranial Doppler ultrasonography (TCDU) was used to measure middle cerebral artery blood velocity and the number of cerebral microembolic events. In one group of patients undergoing CABG, the investigators included an arterial filter in the cardiopulmonary bypass circuit to reduce the number of microemboli reaching the cerebral circulation, whereas the other group of patients underwent CABG without an arterial filter. Patients with an arterial line filter had both fewer intraoperative cerebral microemboli as detected by TCDU, and significantly less neuropsychological deterioration 8 weeks after the operation. Stump and colleagues17 have also provided evidence that microembolic load during CABG is associated with the

development of postoperative neurocognitive deficits. In their study of 167 patients undergoing routine CABG with cardiopulmonary bypass (CPB), they found that patients who exhibited neurocognitive decline 1 week after operation had a significantly greater number of intraoperative cerebral microembolic events than those patients who did not develop postoperative neurocognitive dysfunction. Similarly, Blauth and colleagues18 studied the number of retinal microvascular embolic occlusions after CABG using fluorescin angiography in 20 patients and found that those patients with more microvascular occlusions were more likely to develop postoperative neurocognitive decline 8 days postoperatively. Microemboli generated during CABG may also originate from atherosclerotic disease of the ascending aorta. Using TCDU, Stump and colleagues examined when such microemboli occurred in patients undergoing standard CABG.19 They found that 63.5% of intraoperative emboli occurred during periods in which the surgeon was physically manipulating the heart or aorta. Aortic cannulation and cross-clamp application or removal accounted for most of these microemboli. Similarly, Harringer and coworkers20 deployed an intraaortic filter in patients undergoing CABG with CPB just before removal of the aortic crossclamp. The particulate matter caught by these filters was then examined histologically and 62% of these filters were found to contain fibrous atheroma, while platelet and fibrin strands were found in 52%. Previous investigators have also demonstrated that the microembolic load during routine CABG is heaviest during either aortic cannulation or cross-clamping, indicating that physical manipulation of the aorta is likely a significant source of cerebral microemboli.21 However, in addition to aortic atherosclerosis, shed blood that is returned directly to the patient through the cardiotomy suction results in increased numbers of cerebral microemboli. These microemboli have been shown to produce characteristic small capillary arterial dilatations (SCADS) in the cerebral microvasculature on pathologic examinations of both human and animal brains.22 These SCADS are thought to represent small (10 to 70 ␮m) acellular lipid deposits. Their association with cardiotomy suction has been documented by Brooker and colleagues in a canine model of cardiopulmonary bypass.23 In addition to particulate emboli, gaseous bubbles as-

Neurologic Outcomes After CABG

sociated with cardiopulmonary bypass circuits have been long-recognized as a potential source of both macroembolic and microembolic phenomena during standard CABG.

Cerebral Hypoperfusion Cerebral hypoperfusion is another potential cause of neurologic injury after CABG. Inadequate blood flow to the cerebral parenchyma results in a complex ischemic cascade, which eventually results in lethal injury to the cells that are underperfused. When oxygen delivery is not sufficiently matched with cerebral metabolic rates, high-energy phosphate stores are depleted, which in turn leads to an influx of sodium and calcium anions. As the affected cells become depolarized, glutamate is then released from the cell, which then causes additional voltage-gated calcium channels to open. As calcium continues to influx into the cell, the intracellular calcium concentration increases to levels, which promote proteolysis, lipolysis, destruction of DNA, and eventually cell death. The relative importance of cerebral hypoperfusion as a cause of neurologic dysfunction after CABG is controversial. Although prolonged periods of global cerebral ischemia can certainly cause ischemic damage to so-called watershed areas of cerebral parenchyma, and therefore major stroke, a direct relationship between cerebral perfusion and neurologic injury is not well supported. Although maintenance of perfusion pressure ⬎50 mm Hg during hypothermic CPB appears to be well tolerated by the majority of patients higher pressures have been studied (⬎70 mm Hg). Gold et al24 prospectively examined perfusion pressure in two groups of patients undergoing CABG and demonstrated an improved neurologic outcome in patients perfused between 80 to 100 mm Hg. However, when patients are stratified for the atherosclerotic burden of the ascending aorta, perfusion pressure was not a significant predictor of neurologic outcome.25 In addition, Newman et al26 examined the relationship between intraoperative mean arterial pressure and the incidence of postoperative neuropsychological dysfunction. Multivariable linear regression analysis failed to show an associated between the time and degree of intraoperative hypotension and the development of postoperative cognitive decline, except in a subset of older patients. Mean arterial pressure has been used as a marker of cerebral perfusion pressure

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in several studies that have attempted to clarify the relationship between CBF- and CABG-associated neurocognitive deterioration; however, these studies have generally failed to demonstrate such a causal relationship. In the absence of unequivocal evidence to suggest otherwise there is little reason to alter perfusion practices tolerated by the vast majority of patients.

Neuroprotective Strategies During CABG with CPB Reduction of Cerebral Embolization Several potential strategies may reduce the incidence of stroke and/or neurocognitive dysfunction after CABG with CPB. Inclusion of a filter in the arterial line of the cardiopulmonary bypass circuit purportedly reduces the number of atheromatous and other emboli that reach the cerebral circulation. Pugsley et al27 demonstrated that patients who underwent CPB with a 40-␮m filter included in the arterial line had significantly less neuropsychological deterioration at both 8 days and 8 weeks postoperatively. However, the most efficacious pore size to use is not known, and the use of an arterial line filter will not completely prevent particulate or gaseous emboli from reaching the cerebral arterial circulation, nor is arterial line filtration capable of capturing emboli that arise from the ascending aorta. Nevertheless, arterial line filtration is relatively free of adverse sequelae and should therefore be considered standard practice during cardiopulmonary bypass. Cerebral microembolization occurs during periods of aortic cannulation or clamping, suggesting that these emboli may originate from atherosclerotic lesions of the ascending aorta. The use of intraoperative echocardiography, either transesophageal echocardiography (TEE) of the descending aorta or epiaortic scanning of the ascending aorta before cannulation or clamp placement allows the identification of patients who are at higher risk of emboli generation due to the presence of severe atherosclerotic disease. Epiaortic scanning has been demonstrated to be superior to either standard radiographic methods or manual surgical palpation in detecting the extent of atherosclerotic disease.28 Several groups have confirmed that the severity of aortic atheromatous disease as determined by TEE is strongly associated with the development of post-

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operative neurologic dysfunction, especially if the aortic atheromatous plaques are mobile in nature. Hartmann and colleagues performed TEE in 189 patients undergoing CABG.25 They found that those patients with grade III or higher aortic atherosclerotic disease (ie, the presence of a protruding atheroma with or without mobile components) had a significantly higher incidence of stroke one week postoperatively (5.5% of grade III patients, 10.5% of grade IV patients, and 45.5% of grade V patients) than patients with grade I or II disease (intimal thickening only with no protruding atheroma), in whom there were no postoperative strokes. In addition by specifically assessing the ascending aorta by epiaortic scanning before aortic instrumentation, the surgeon may locate relatively nondiseased portions of the aorta at which the cannula and clamp may be placed, thereby reducing the risk of disrupting atheromatous lesions of the aorta and subsequent generation of emboli. Recognition of ascending aortic atherosclerosis as a primary source of cerebral emboli has also led some groups to argue for the standard use of a single aortic cross-clamping technique. Calafiori and colleagues reviewed the neurologic outcomes of CABG patients in whom CPB was performed and demonstrated that the use of side clamp was an independent predictor for the development of postoperative stroke.29 Similar findings were obtained by Aranki et al30 in a study of 160 patients undergoing single cross-clamping compared with 150 patients undergoing double clamping with a partially occluding side-clamp placed during proximal aortic anastomoses. Moreover, this group found that there were no adverse myocardial-related sequelae resulting from single clamping. However, not all analyses support the superiority of single aortic clamping in preventing stroke, and no prospective, randomized trials have yet been performed which assess the impact of clamping technique on neurocognitive outcome. For those patients in whom the entire ascending aorta is severely diseased alternative strategies may be considered. In one prospective study, the internal mammary artery was used as the sole inflow source for saphenous vein grafts and resulted in a significantly lower incidence of neurocognitive dysfunction 2 months postoperatively (3.8%) than if standard aorto-coronary anastomoses were performed (38%). Use of the ‘no touch’ technique, in which aortic clamping is avoided

during CPB by inducing fibrillatory arrest electrically and using only pedicalized arterial conduits, have also resulted in relatively low rates of postoperative neurologic injury in several small studies of patients with heavily calcified ascending aortas.31 Finally, the use of cardiotomy suction has also come under scrutiny as a potential source of lipid microemboli. Evidence for such microemboli come from the presence of SCADS, found within the cerebral arterial vasculature of patients who have undergone coronary artery bypass surgery using CPB. In a canine study, Brooker and colleagues22,23 found that the number of SCADS detected in the brain parenchyma was 10-fold greater in dogs that had undergone CPB using cardiotomy suction than in dogs who underwent CPB without cardiotomy suction. In a prospective, randomized, study of patients undergoing CABG, Aldea et al32 demonstrated a reduction in systemic procoagulant and proinflammatory factors when shed blood was not returned via a cardiotomy reservoir.

Hypothermia Maintaining hypothermia during CPB has long been recognized as a potential neuroprotective measure. At modest levels of hypothermia (32-35°C), cerebral metabolic rate and cerebral blood flow are tightly coupled, such that any decrease in CBF, which is a typical occurrence during CPB, is met with an automatic reduction in cerebral metabolism and therefore oxygen demand. Moreover, even mild reductions in cerebral perfusion temperature have been shown to reduce high-energy phosphate depletion and excitatory neurotransmitter release. These molecular effects of hypothermia have translated into a reduction in infarct size in animal models of cerebral ischemia.33 However, several groups have found no increase in the incidence of postoperative neurologic injury during normothermic CPB when compared with moderately hypothermic CPB. In a randomized trial of 227 patients Grigore et al34 demonstrated no improvement in 6-week neurologic or neurocognitive outcomes using hypothermic (28-30°C) versus normothermic (30-35°C). CPB. Conversely, other investigators have demonstrated compromised neurologic outcome when normothermic CPB is used. In one study of 138 patients who were prospectively randomized to undergo either hypothermic (⬍28°C) or normothermic (⬎35°C) CPB, Mora and col-

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leagues found that the incidence of postoperative stroke was significantly greater in the normothermic patients.35 The studies of neurologic outcome after hypothermic versus normothermic CPB for CABG, when considered collectively, do not clearly establish hypothermic CPB as a neuroprotective strategy. However the standard practice of hypothermia during CPB will likely continue despite these conflicting trial outcomes.

Rate of Rewarming The rate and extent of rewarming from hypothermic CPB can promote neurologic injury. Several groups have shown that rapid rates of rewarming after hypothermic CPB resulted in reduced jugular venous oxygen saturation, presumably a result of increased cerebral metabolism and thus elevated oxygen extraction levels within the cerebral circulation. These findings are in addition to the already well-documented deleterious neurologic effects of hyperthermia.36 Grigore and colleagues have linked rapid rewarming rates and cerebral hyperthermia to postoperative neurocognitive decline.37 In this prospective study, patients were randomized to either conventional rewarming methods (maintenance of a 4-6°C gradient between nasopharyngeal temperature and CPB perfusate temperature, n ⫽ 100), or slow rewarming methods (maintenance of a 2°C or smaller gradient, n ⫽ 65). These investigators found that use of the slow rewarming method resulted in significantly better neurocognitive function 6 weeks postoperatively than if more rapid rewarming was performed. This same group of investigators performed subsequent study in which 300 consecutive patients undergoing CPB for CABG had hourly postoperative temperatures recorded for 24 hours. Patients found to have higher maximum postoperative temperatures had a significantly greater incidence of cognitive dysfunction 6 weeks postoperatively. Slower rewarming rates and careful avoidance of hyperthermia should be practiced routinely in all patients undergoing CPB.

pH Management Strategy Hypothermia reduces the solubility of gases, such as CO2, in blood. Therefore, at the lower systemic temperatures used in hypothermic CPB, the partial pressure of CO2 (PaCO2) in arterial blood is relatively low, meaning the patient is relatively alka-

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lotic. The higher pH that results causes the oxyhemoglobin dissociation curve to shift to the left, resulting in decreased oxygen availability to brain tissue, and a cerebral vasoconstrictive effect, which leads to reduced cerebral blood flow. There are two possible acid-base management strategies during hypothermic CPB. In the pH stat method, the effects of reduced temperature on PaCO2 are taken into account and exogenous CO2 is provided to the patient in an effort to restore both PaCO2 and pH to normal, nonhypothermic levels. In the alpha stat method, PaCO2 is allowed to remain low and pH allowed to remain high. Which method is best for adult patients undergoing hypothermic CPB has been the focus of considerable debate. In the alpha stat method, CBF is reduced, but pressure-flow autoregulation is still maintained such that the reduction in CBF is met with a proportional decrease in cerebral metabolic rate. In the pH stat method, CBF is relatively higher, but pressure-flow autoregulation is lost. Furthermore, when the patient is rewarmed, the solubility of CO2 in blood increases back to normal levels, producing a relative acidosis. Finally, the increased CBF associated with the pH stat method may also increase the delivery of microemboli to brain tissue.38 Several prospective clinical trials have been performed to determine which of these acid-base management strategies produced the best neurologic outcome. The largest such trial was performed by Murkin and colleagues on 316 patients undergoing CABG with hypothermic (28°C) CPB. Patients were randomized to either a pH stat or alpha stat acid-base management strategy. Neuropsychological testing 2 months postoperatively demonstrated that patients who were managed using the alpha stat had significantly improved neurocognitive functioning.38 These findings have been duplicated by several smaller studies.39,40 In addition, while cerebral blood flow may be lower with the alpha stat method, this method preserves pressure-flow autoregulation whereas the pH stat method does not. Based on these prospective, randomized trials, alpha stat acid-base management has become the standard strategy for CABG patients undergoing hypothermic CPB.

Off-Pump CABG (OPCAB): Influence on Neurologic Outcome Interest in performing coronary bypass surgery without cardiopulmonary bypass has undergone resurgence in the last several years. Large retro-

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spective analyses of surgeons’ experiences with OPCAB have shown that this procedure is capable of reducing postoperative morbidity and mortality. Using the Society of Thoracic Surgeons National Adult Cardiac Surgery Database, Cleveland and colleagues reviewed the outcomes of 11,717 OPCAB procedures performed at 126 centers across the country from January 1998 to December 1999. These results were compared with 106,423 standard on-pump procedures performed during the same time period. The authors found that OPCAB patients had a significant reduction in risk-adjusted in-hospital mortality (2.3% in the off-pump patients versus 2.9% in the on-pump patients) and the rate of major complications (10.6% versus 14.2%), including a reduction in neurologic sequelae.41 Similar reductions in in-hospital mortality and morbidity were obtained when 680 OPCAB patients were retrospectively compared with 1773 on-pump procedures using the Department of Veterans Affairs Continuous Improvement in Cardiac Surgery Program database.42 Given the prominent role of CPB in causing neurologic injury during CABG, widespread adoption of OPCAB result in improved neurologic outcome due to both a reduction in cerebral emboli generation as well as an avoidance of prolonged periods of cerebral hypoperfusion. However, comparisons of postoperative stroke rate in patients undergoing OPCAB to standard CABG with CPB have failed to demonstrate significant reductions in postoperative stroke rate.43-46 In a retrospective review of 1389 standard CABG patients and 483 OPCAB patients, Ricci found that CPB was a significant predictor of stroke in univariate but not multivariate regression analysis.43 Similar findings were reported by Hernandez who found that the postoperative stroke rate after OPCAB (1.33%) was not significantly different from that after CABG with CPB (1.82%).44 Conversely, when specific populations of patients who are at high risk for perioperative stroke are considered, the existing literature does indicate a possible reduction in stroke incidence following OPCAB. Ricci and colleagues43 reviewed outcomes in 97 OPCAB patients and 72 standard CABG patients who were 70 years of age or older. The incidence of stroke was significantly lower in OPCAB patients than in patients undergoing standard CABG. These findings were corroborated by Hirose in a study of patients

older than 75 years of age.47 In a high risk group (diabetes mellitus, heavily calcified ascending aortas, and reoperations) Abraham showed that the incidence of stroke was reduced from 3.6% in patients undergoing CPB to 1.2% in patients receiving undergoing off-pump revascularization.48 Thus, although large retrospective studies have failed to show a reduction in postoperative stroke rate after OPCAB when compared with CABG with CPB, the elimination of CPB does appear to significantly reduce the incidence of type I neurologic injuries in patients who are at higher risk for such complications. The ability of investigators to detect a reduction in stroke rate after OPCAB may be limited by both the relatively low incidence of this complication, and the difficulty in implementing a prospective, randomized trial using a population that is large enough to detect such a benefit.

Neurocognitive Outcomes After OPCAB OPCAB has been shown to reduce the number of cerebral microemboli generated during coronary surgery. In a prospective trial, Diegler performed TCDU in 40 patients randomized to receive either off-pump or on-pump coronary artery surgery. Patients in the off-pump group had significantly fewer emboli (median ⫽ 11) compared with patients in the on-pump group (median ⫽ 394.5).49 Similar reductions in the number of cerebral microemboli generated during OPCAB when compared with CABG with CPB have been reported by other authors.50,51 The relationship between cerebral microemboli and neurocognitive outcome has led to speculation regarding the potential benefit of OPCAB. In addition to microemboli, Diegler et al49 assessed early postoperative cognitive function. Of the patients undergoing CABG with CPB 90% demonstrated some degree of cognitive impairment, whereas cognitive function was preserved after OPCAB. Bhasker Rao et al51 correlated a reduction in microemboli with improved frontal lobe function as measured by antisaccidic eye movement after OPCAB. Murkin compared OPCAB to patients undergoing CABG with CPB. A significant reduction in neurocognitive dysfunction from 90-66% at discharge and 50-5% at 3 months was observed in the OPCAB patients.52 In a recent study at our institution we prospectively compared 48 OPCAB patients to conventional CABG (S-CABG) matched for age, gender, number of grafts, and date of

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Figure 2. Comparison of mean cerebral embolic counts between OPCAB and S-CABG patients. *P ⬍ 0.0001 (versus S-CABG group) using Wilcoxon two-sample rank sum test.

surgery. An overall cognitive function score was determined preoperatively and six weeks following surgery from a battery of neurocognitive tests. A cognitive deficit was defined as at least a one standard deviation decline in any of the four independent cognitive domains and occurred in 40% of the S-CABG group. A significant reduction in neurocognitive dysfunction (17.1%) was seen in patients following OPCAB procedures as shown in Fig 2. In contrast, several investigators have failed to demonstrate an improvement in cognitive function following OPCAB. Taggert found no difference in cognitive function in patients after OPCAB or CABG with CPB, three months postoperatively.53 Two randomized trials have also addressed this issue. Lloyd randomized 60 patients to either OPCAB or standard CABG, assessing neurocognitive function at 12 weeks postoperatively and found no change in neurocognitive performance between the two groups.54 A second prospective trial assessing neurocognitive outcome after OPCAB or CABG with CPB also casts doubt on the presumed superiority of the off-pump approach. This trial randomized 142 patients to OPCAB and 139 patients to standard CABG, after which neurocognitive performance was assessed at both 3 and 12 months postoperatively. The incidence of neurocognitive dysfunction was lower in the OPCAB group (21%) at 3 months, compared with the on-pump group (29%). At 12 months, 30.8% of off-pump patients and 33.6% of on-pump patients experienced some degree of neurocognitive decline, a difference that was not statistically significant. Further analysis failed to show a difference in quality of life between the two groups.55

Thus, although off-pump CABG is associated with a reduction in the number of intraoperative cerebral microemboli, a clear relationship between the reduction in microemboli and improvement in neurocognitive function remains inconclusive. To reconcile these discrepancies several considerations are necessary. The first is that no true neurologic or neurocognitive outcomes benefit from OPCAB exists. However, the consistent reduction in microemboli and the lower stroke rate in high risk groups argue against this conclusion. Both randomized trials included patients whose the mean age was approximately 60 years, and the study populations had less advanced coronary artery disease and limited comorbidity. Since the risk of both type I and type II neurologic injury is greatest for older patients or those with extensive co morbidities such as diabetes or peripheral vascular disease,30 further investigation needs to be performed to determine if OPCAB has greater benefit for higher risk patient populations. In addition, the Van Dijk trial was powered to detect a two-thirds reduction in cognitive decline in the OPCAB group at three months postoperatively. Clearly, larger trials are needed if smaller reductions in the incidence of cognitive deterioration are to be detected. Finally, as Newman has shown because neurocognitive dysfunction after CABG may worsen beyond one year, longer follow-up may be required to detect a benefit.26 Technical advances may further improve the neurologic outcomes after OPCAB. Cardiac displacement to gain access to the posterior cardiac wall during OPCAB causes a transient elevation in central venous pressure and a simultaneous decrease in systolic blood pressure.56 Even with-

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out CPB, transient periods of cerebral hypoperfusion are possible during OPCAB. Embolic events may occur due to placement of the partial occlusion aortic clamp necessary to perform proximal graft anastomoses. OPCAB, in its present form, does not entirely eliminate the possibility of either cerebral microembolism or cerebral hypoperfusion. Further refinements in off-pump techniques are being developed. Recent introduction of an automated proximal anastomotic device has allowed the elimination of both CPB and aortic cross clamping.57 This ability to minimize aortic manipulation during CABG may have beneficial effects with respect to cerebral microemboli generation. We have recently performed OPCAB procedures in 53 patients using an automated anastomotic device for all proximal vein graft anastomoses (106 total proximal anastomoses). In a subset of these patients, we performed TCDU to determine intraoperative cerebral microembolic counts. We compared these counts with those measured in a similar group of patients undergoing standard CABG with CPB. We found that the combined use of off-pump techniques and a sutureless proximal aortic anastomotic device reduced the number of cerebral microemboli nine-fold when compared with patients receiving standard CABG with CPB and hand

sewn proximal anastomoses (Fig 3). Thus, novel technologies such as the sutureless proximal anastomotic devices and other enabling technology to allow clampless surgery may enable the cardiac surgeon to extend the benefits of offpump coronary artery surgery. Further investigations are needed to determine whether these or other such strategies significantly reduce the incidence of neurologic injury after CABG.

Summary Neurologic injury after CABG remains a significant problem that is likely to increase as coronary surgery is being performed on older patients with greater comorbidity. The etiology of neurologic injury after CABG is multifactorial, with cerebral embolism and hypoperfusion playing the largest roles. Several important neuroprotective strategies have been developed to minimize injury during CABG with CPB. The optimal perfusion characteristics have yet to be defined; however, the use of hypothermia, alpha stat acidbase management, and slow patient rewarming with the avoidance of hyperthermia have been shown to result in improved neurologic outcome after CPB. Technical strategies, including the use of intraoperative echo to assess aortic atherosclerotic disease and subsequent sites of aortic

Figure 3. Changes in cognitive function at 6 seeks. *P ⫽ 0.03, denotes change compared with baseline.

Neurologic Outcomes After CABG

cannulation, and the use of single aortic crossclamping, may also improve neurologic outcomes. Off-pump CABG has been shown to reduce the number of cerebral microemboli generated during coronary revascularization. Large retrospective reviews of patients undergoing OPCAB demonstrate that the risk of stroke may be reduced, especially in the elderly or otherwise high-risk patients. The prospective randomized trials that have been performed to date examining the neurocognitive outcomes associated with OPCAB have shown conflicting results compared with onpump CABG. However, larger, multicenter, randomized trials are required, with consideration given to high risk study populations. Moreover, recent modifications to the OPCAB procedure, and the ability to perform clampless aortic anastomoses, hold promise in their potential to further minimize the neurologic complications associated with CABG.

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